Pemphigus vulgaris (PV) is a life-threatening mucocutaneous autoimmune blistering disease. We previously showed that genetic variants within the ST18 gene promoter area confer a 6-fold increase in the propensity to develop PV. ST18, a transcription factor, was found to be overexpressed in the epidermis of PV patients. In addition, it was found to promote autoantibody-mediated abnormal epidermal cell-cell adhesion as well as secretion of pro-inflammatory mediators by keratinocytes.We aimed at delineating the mechanism through which ST18 contributes to destabilization of cell-cell adhesion.We used qRT-PCR, immunofluorescence microscopy, a luciferase reporter system, site-directed mutagenesis, chromatin immunoprecipitation (ChIP) and the dispase dissociation assay.Chromatin immunoprecipitation (ChIP) and luciferase reporter assays showed that ST18 directly binds and activates the TNF promoter. Accordingly, increased ST18 expression contributes to PV pathogenesis by destabilizing cell-cell adhesion in a TNFα-dependent fashion. In addition, dual immunofluorescence staining showed increased expression of both ST18 and TNFα in the skin of PV patients carrying a ST18-associated PV risk variant which was found to be associated with a more extensive PV phenotype.Our findings suggest a role for TNFα in mediating the deleterious effect of increased ST18 expression in PV skin.